Summary Nervous systems process information by integrating the electrical activity of neurons in complex networks. The alterations in the ?flow? of electrical activity through neuronal networks of the brain play a causal role in the pathogenesis and/or the appearance of symptoms of neurodegenerative and psychiatric diseases. A fundamental goal of BRAIN Initiative is therefore to elucidate how the brain's neural circuits are structurally and functionally connected, a prerequisite for hypotheses- guided developments of more effective pharmacological treatments of these diseases. Unfortunately this goal remains elusive at present, largely due to the lack of technology to perform scalable recording and manipulation of neural activity with high S/N ratio, at single-cell level, over long period of time and under physiological conditions. The classic method of electrophysiology requires physical contact and electrical coupling between the recording electrodes and the cells under investigation, which presents different challenges regarding the two primary forms of technologies currently available. Intracellular recording methods by sharp electrode or patch clamping constrains the measurement to one cell at a time, and limits the recording time to several minutes due to the invasive nature of this approach. Extracellular recording with parallel, planar electrode array lacks single cell resolution, and fails to detect subthreshold synaptic potentials. The absence of adequate environmental control for both methods further reduces the physiological relevance of the results. The novel electrophysiology platform proposed in this STTR application aims to provide a powerful solution that bridges the long-standing gap between high-quality, non-scalable intracellular electrophysiology and low-quality, scalable extracellular electrophysiology; so to enable for the first time simultaneous, noninvasive measurement of intracellular membrane potential from many neurons under optimal physiological conditions. Central to this platform is the seamless integration of two innovative approaches: 1) parallel, nano-fabricated biocompatible electrodes, and 2) sensitive, environmentally robust electronics. We also plan to validate the complete system for analyzing neural network, using in vitro culture of cortical neurons. In summary, the ability to monitor the activities of larger neuronal networks simultaneously and non-invasively is a necessary prerequisite to understanding how neuronal networks function at the systems level. Our breakthrough technology is well positioned to provide a significantly improved cellular electrophysiology system for large-scale recording and manipulation of neural activity, with an immediate and positive impact on BRAIN Initiative?s central objective to understand the dynamic activity of neural circuits. This system, with further development, can support recording from even larger number of neurons, of different types, and for other applications such as neurotoxicity evaluation for drug development.